A straightforward one-pot multicomponent synthesis of polysubstituted pyrroles

Article abstract of DOI:10.1039/c1cc11363a

Polysubstituted pyrroles were efficiently synthesized in moderate yields by a one-pot multicomponent reaction starting from primary amines, ethyl glyoxalate and 2-bromoacetophenones in the presence of pyridine in refluxing acetonitrile. This methodology w

Full text of DOI:10.1039/c1cc11363a

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COMMUNICATION
A straightforward one-pot multicomponent synthesis of polysubstituted
pyrrolesw
Xufeng Lin,* Zhenjun Mao, Xixiang Dai, Ping Lu and Yanguang Wang*
Received 9th March 2011, Accepted 15th April 2011
DOI: 10.1039/c1cc11363a
Polysubstituted pyrroles were efficiently synthesized in moderate
yields by a one-pot multicomponent reaction starting from primary
amines, ethyl glyoxalate and 2-bromoacetophenones in the presence
of pyridine in refluxing acetonitrile. This methodology was utilized
to synthesize a highly substituted benz[g]indole.
also synthesised from 1,3-dicarbonyl compounds, amines,
aldehydes, and nitroalkanes via an iron-catalyzed MCR.13
As part of our current studies on multicomponent synthesis
of heterocycles,14 we were interested in the straightforward
construction of a 1,2,3,5-tetrasubstituted pyrrole ring via a
four-component reaction (Scheme 1), involving the assembling
of the pyrrole core from [2+1+1+1] atom fragments and the
formation of four new bonds. We herein report the results of
this effort.
Pyrrole derivatives are an important class of organic compounds.
They are structural units of many natural products and
important pharmaceuticals and useful building blocks for
various biologically active molecules and functional materials.1
As the world’s leading cholesterol-lowering drug, atorvastatin
calcium (Lipitor) is a prime example.2 Consequently, the
construction of pyrrole rings bearing diverse substitution
patterns has received much attention.3 Conventional methods
for the preparation of polysubstituted pyrroles include the
Hantzsch and Paal–Knorr reactions.4 A variety of transition-
metal catalyzed strategies were also developed over the last
decade.5 Although the literature on pyrrole synthesis enjoys a
rich history of versatile methodologies, new direct approaches
remain highly valuable to the contemporary collection of
synthetic strategies due to the continued importance of the
pyrrole core in both biological and chemical fields.
Exhaustive studies of the reaction conditions for the
synthesis of 4a from p-methoxyphenyl amine (1a) with ethyl
glyoxalate (2) and phenacyl bromide (3a) in the presence of
pyridine were conducted (Table 1). It was found that aceto-
nitrile was the most suitable solvent for this transformation
among others, such as dichloroethane (DCE), THF and
toluene (Table 1, entries 1–4). Then, we moved on to screen
the reaction temperatures. Much lower yields were observed
when the reaction temperature was decreased below reflux
temperature (Table 1, entries 5 and 6). Furthermore, it was
found that additives with 4 A MS, TEA, DBU, DABCO and
Na2CO3 were ineffective to improve the yield (Table 1, entries
7–11). Thus, the most suitable reaction conditions for
the formation of 4a were established (Table 1, entry 2).
It is notable that the reaction proceeded smoothly without
exclusion of moisture or air.
Multicomponent reactions (MCRs) have emerged as a
powerful strategy in organic, combinatorial, and medicinal
chemistry.6 Various MCRs have been developed not only for
their facileness and efficiency, but also for their economy and
ecology in organic synthesis.7 These features make MCRs
well-suited for the easy construction of diversified heterocyclic
scaffolds.8 Actually, MCRs have been demonstrated as a
straightforward approach to pyrroles,9 which have been
extensively reviewed.10 More recently, Parrain et al. developed
the palladium and copper catalyzed synthesis of trisubstituted
pyrroles via the MCR of 3,4-diiodoalk-2-enoic derivatives,
primary amines, and terminal alkynes.11 Zhu et al. reported
a MCR/post-functionalization strategy for the synthesis of
2-amino-5-cyanopyrroles.12 The functionalized pyrroles were
With the optimized reaction conditions in hand, we next
explored the protocol with a variety of primary amines 1 and
2-bromoacetophenones 3 (Table 2). The primary aromatic
amines reacted well, providing the pyrrole products in
42–64% yields (Table 2, entries 1–5). The electron-donating
as well as electron-withdrawing groups on aromatic rings were
tolerated, although the latter gave slightly reduced yields. In
contrast, the reactions of aliphatic primary amines including
cyclohexylamine (Table 2, entry 6), benzylamine (Table 2,
entry 7) and n-butylamine (Table 2, entry 8) afforded the
Department of Chemistry, Zhejiang University, Hangzhou 310027,
China. E-mail: lxfok@zju.edu.cn, orgwyg@zju.edu.cn
w Electronic supplementary information (ESI) available: Experimental
procedure, 1H and 13C NMR spectra for all compounds. CCDC
798900 and 801307. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1cc11363a.
Scheme 1 Multicomponent approach to pyrroles.
c
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Table 1 Optimization of reaction conditions of the multicomponent
reactiona
or an electron-donating group (Table 2, entries 15–18) on the
aryl ring could smoothly afford the desired products in
32–70% yields.
The structures of products 4a–4t were characterized
by 1HNMR, 13CNMR, IR, MS and HRMS spectra. The
structure of compound 4a (Table 2, entry 1) was unambiguously
confirmed by single-crystal X-ray analysis.15 The unusual
structure feature for our products 4 is that the aroyl substituent
is at the 2-position of the pyrrole ring, which is different from the
products of the Hantzsch-type reaction.
Entry
Solvent
Additive
T/1C
Time/h
Yieldb (%)
A possible mechanism for this tandem reaction is postulated
in Scheme 2. Firstly, phenacyl bromide 3a reacts with pyridine,
followed by deprotonation to form pyridinium ylide B, while
imine C is in situ generated from amine 1a and ethyl glyoxylate
(2). Secondly, B nucleophilically attacks C via a Mannich
addition, followed by an intramolecular nucleophilic
substitution to form aziridinium bromide E. Then, E is
attacked by B to form F. The resulting pyridinium salt F
undergoes an elimination of pyridinium, followed by an
intramolecular nucleophilic addition to yield dihydropyrrole
H. Finally, dehydration of H affords pyrrole 4a.
1
2
3
4
5
6
DCE
CH3CN
THF
—
—
—
—
—
—
4 A MS
TEA
DBU
DABCO
Na2CO3
Reflux
Reflux
Reflux
Reflux
50
12
12
12
12
24
24
12
12
12
12
12
55
64
Trace
42
33
28
64
30
35
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
25
7c
8d
9d
10d
11d
Reflux
Reflux
Reflux
Reflux
Reflux
Trace
55
a
All the reactions were carried out using 1a (1 mmol), 2 (1 mmol), 3a
b
(2.2 mmol), and pyridine (5 mmol) in 5 mL of solvent. Isolated
c
d
yields. 0.1 g of 4 A MS was used. Pyridine (3 mmol) and additive
(2 mmol) were used.
One interesting application of this methodology is the ready
access to a new benz[g]indole derivative. A demonstration of
the synthetic utility for this method is shown in Scheme 3.
Thus, treatment of 5a (1.0 eq.), which was derived by the
hydrolysis of pyrrole 4a, with 1,2-diphenylethyne (1.2 eq.) in
Table 2 One-pot multicomponent reactions for the synthesis of
pyrrolesa
Entry
R
Ar
4
Yieldb (%)
1
2
3
4
5
6
7
8
4-MeOC6H4 (1a)
4-MeC6H4 (1b)
Ph (1c)
4-ClC6H4 (1d)
4-BrC6H4 (1e)
Cyclohexyl (1f)
Bn (1g)
n-Bu (1h)
1a
1b
1c
1d
1e
1g
1a
1c
1e
1g
1a
1d
Ph (3a)
3a
3a
3a
3a
3a
3a
3a
4-ClC6H4 (3b)
3b
3b
3b
3b
3b
4-MeC6H4 (3c)
3c
3c
3c
4-BrC6H4 (3d)
3d
4a
4b
4c
4d
4e
4f
4g
4h
4i
64
58
50
42
45
35
38
28
70
61
52
50
48
40
52
48
40
32
55
41
9
10
11
12
13
14
15
16
17
18
19
20
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
a
All the reactions were carried out using 1 (1 mmol), 2 (1 mmol), 3
b
(2.2 mmol), and pyridine (5 mmol) in CH3CN (5 mL). Isolated yields.
desired products in lower yields (28–38%). On the other hand
the 2-bromoacetophenone substrates 3 bearing either an
electron-withdrawing group (Table 2, entries 9–14, 19 and 20)
Scheme 2 Proposed mechanism for the synthesis of pyrrole.
Chem. Commun., 2011, 47, 6620–6622 6621
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the presence of Pd(OAc)2 (0.05 eq.), Cu(OAc)2ÁH2O (2.0 eq.),
LiOAc (4.0 eq.), and 4 A molecular sieves in DMAc afforded
benz[g]indole 6a16 in 84% yield. The reaction is proposed to
proceed via a palladium-catalyzed oxidative decarboxylative
coupling reaction of 5a with 1,2-diphenylethyne.17 This
cascade approach to highly substituted benz[g]indoles is
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In conclusion, we have developed a one-pot synthesis of
polysubstituted pyrroles via the multicomponent reaction of
primary amines, ethyl glyoxalate and 2-bromoacetophenones.
The reaction involves the assembling of [2 + 1 + 1 + 1] atom
fragments and the formation of four new bonds. The starting
materials are readily available. By combining with a palladium-
catalyzed oxidative decarboxylative coupling reaction, this
chemistry provides a rapid access to a highly substituted
benz[g]indole.
We thank the National Natural Science Foundation of
China (No. 21032005 and 20702047) and Zhejiang Provincial
Natural Science Foundation of China (Y4090028 and
R407106) for financial support of this research.
Notes and references
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6622 Chem. Commun., 2011, 47, 6620–6622
This journal is The Royal Society of Chemistry 2011